Pain is a very common clinical problem, causing suffering in millions of people. Treatment of pain that lasts longer than a brief procedure can be difficult and can entail the use of opioids, with their side effects and potential for addiction and diversion. In this research we seek to develop injectable drug delivery systems (DDS) using sustained release technology to provide continuous prolonged duration local anesthesia (PDLA) lasting many hours to days for perioperative pain, or even weeks for chronic pain. In addition, we are developing DDS where the patient could determine when she or he receives local anesthesia, how intense the anesthesia is, and how long it lasts. Those on-demand DDS (termed triggered local anesthetics) are controlled by external energy sources such as near-infrared light and ultrasound. Both the continuous and triggered DDS have the potential to revolutionize pain management, and advance the science of drug delivery. They could also mitigate or obviate opioid use. All the DDS should ideally: be delivered by a single injection; be easy to administer; not require general anesthesia or surgery to initiate; last days-weeks; cause no local inflammation, local neuro- or myotoxicity, or systemic toxicity; be fully biodegradable and reversible; be cost effective, easy to make, and stable. Triggerable systems should be easy to use with a safe and convenient device. Our strategy has been to use sustained release vehicles to deliver site 1 sodium channel blockers (S1SCBs) such as saxitoxin and tetrodotoxin in combination with compounds that are known to enhance their duration of nerve blockade, such as conventional local anesthetics and steroids. In PDLA, we have achieved a liposomal formulation containing S1SCBs and other drugs, which can achieve sciatic nerve blocks in the rat lasting a week with minimal systemic and local toxicity. In triggered local anesthesia, we have produced liposomes containing S1SCBs and other drugs which produce an initial nerve block that resolves, after which nerve block can be safely and repeatedly re-induced by targeting the injection site with near-infrared light or ultrasound. This work produced 31 papers in the past 5 years, many in prominent journals. In PDLA, we propose a spectrum of potential approaches to produce yet longer blocks while improving safety. In triggered LA, we propose means to modulate or negate the initial nerve block, extend the number of triggerable events, and extend the time frame over which they can be triggered ? allowing use in chronic pain. Addressing these challenges will entail overcoming challenges in biomaterials / drug delivery / nanoscience, including enhancing the loading of highly water-soluble charged drugs in DDS, minimizing their initial rapid (?burst?) release, extending their duration of release, and /or minimizing their baseline (un-triggered) release. Importantly, the impact of new approaches on tissue reaction will be studied, using histological and toxicogenomic approaches.